Hopkins County and Madisonville were divided by the Civil War. Union supporters joined a regiment recruited locally by James Shackleford; Al Fowler recruited Confederate troops. The courthouse in Madisonville was burned by Confederates led by Gen. Hylan B. Lyon on December 17, 1864, as they passed through western Kentucky. The policies imposed by the occupying Union armies caused resentment and sparked sympathy for the Confederate cause.

Farming was the major occupation in Hopkins County for most of the 1800s, with tobacco the leading crop. Around 1837 an outcropping of coal was discovered and the first coal mine in the county opened in 1869. Mining did not become a major industry until the Louisville & Nashville Railroad pushed its line southward from Henderson through Madisonville and toward Nashville in 1870. By the early 1900s, Madisonville was a rail hub, coal mining center, and had a large tobacco market. This continued until the 1960s when manufacturing and service industries came to the area.

On November 15, 2005, a tornado ripped through the city, destroying some parts of it. The tornado began to form around 3:00 PM. The neighborhood near Madisonville Country Club was greatly affected by the storm. The home of Madisonville resident and former Boston Celtics star Frank Ramsey was destroyed in the storm. Mayor Karen Cunningham ordered a curfew in parts of the city and declared a state of emergency.

In January 2009, a severe ice storm hit Madisonville. Hopkins County and much of the rest of state of Kentucky were affected. Madisonville was placed under a curfew for the safety of the citizens. The storm was responsible for widespread power outages and damage to homes as well as trees. Many residents were without power for weeks and tree limb clean-up took months to complete. Many out-of-state power companies assisted the local power companies to speed up the process of re-powering the town.